Journal of the American College of Cardiology
© 2013 by the American College of Cardiology Foundation
Published by Elsevier Inc.
Vol. 61, No. 11, 2013
ISSN 0735-1097/$36.00
http://dx.doi.org/10.1016/j.jacc.2012.08.1039
STATE-OF-THE-ART PAPER
Paravalvular Leak After
Transcatheter Aortic Valve Replacement
The New Achilles’ Heel? A Comprehensive Review of the Literature
Philippe Généreux, MD,*†‡ Stuart J. Head, MSC,§ Rebecca Hahn, MD,*† Benoit Daneault, MD,*†
Susheel Kodali, MD,*† Mathew R. Williams, MD,*† Nicolas M. van Mieghem, MD,储
Maria C. Alu, MM,* Patrick W. Serruys, MD, PHD,储 A. Pieter Kappetein, MD, PHD,§
Martin B. Leon, MD*†
New York, New York; Montréal, Québec, Canada; and Rotterdam, the Netherlands
Paravalvular leak (PVL) is a frequent complication of transcatheter aortic valve replacement (TAVR) and is seen
at a much higher rate after TAVR than after conventional surgical aortic valve replacement. Recent reports indicating that PVL may be correlated with increased late mortality have raised concerns. However, the heterogeneity of methods for assessing and quantifying PVL, and lack of consistency in the timing of such assessments, is
a hindrance to understanding its true prevalence, severity, and effect. This literature review is an effort to consolidate current knowledge in this area to better understand the prevalence, progression, and impact of post-TAVR
PVL and to help direct future efforts regarding the assessment, prevention, and treatment of this troublesome
complication. (J Am Coll Cardiol 2013;61:1125–36) © 2013 by the American College of Cardiology Foundation
Transcatheter aortic valve replacement (TAVR) has become
the treatment of choice for inoperable patients with severe
aortic stenosis (1) and is comparable to surgical aortic valve
replacement (SAVR) for patients at high risk (2). However,
paravalvular leak (PVL) is more frequently seen after TAVR
than after SAVR, and its potential association with mortality has raised concerns (3– 6). Moreover, recent reports have
suggested that PVL could negatively impact mid- and
long-term prognosis following TAVR (7,8). Although concerning, the lack of standardized quantitative and qualitative
methods to assess and categorize PVL and the heterogeneity in the timing of post-procedural assessment of PVL
warrant caution in interpretation of these data. Therefore,
we sought to perform a systematic review of the current
literature to better define the rate, progression over time,
From the *Columbia University Medical Center/New York Presbyterian Hospital,
New York, New York; †Cardiovascular Research Foundation, New York, New York;
‡Hôpital du Sacré-Coeur de Montréal, Montréal, Québec, Canada; §Department of
Cardiothoracic Surgery, Erasmus University Medical Center, Rotterdam, the Netherlands; and the 储Department of Cardiology, Erasmus University Medical Center,
Rotterdam, the Netherlands. Dr. Généreux has received speaker honoraria, consulting
fees, and research grants from Edwards Lifesciences. Dr. Kodali has received
consulting fees from Edwards Lifesciences and St. Jude Medical. Dr. Kappetein is
member of a steering committee of the SURTAVI (Surgical Replacement and
Transcatheter Aortic Valve Implantation) trial sponsored by Medtronic. Dr. Leon is
a nonpaid member of the scientific advisory board of Edwards Lifesciences. All other
authors have reported that they have no relationships relevant to the contents of this
paper to disclose. Drs. Généreux and Head are joint first authors.
Manuscript received June 27, 2012; revised manuscript received August 7, 2012,
accepted August 21, 2012.
predictors, and consequences of PVL after TAVR. Furthermore, recommendations for measuring PVL are provided to
improve consistency throughout the literature.
Rate of PVL
Multiple studies have reported the frequency and severity of
PVL after TAVR (9). There is, however, significant heterogeneity that is caused by differences in: 1) imaging modalities (transthoracic echocardiography, transesophageal echocardiography, angiography); 2) timing of assessment
(immediately after implantation, before discharge, at 30
days); 3) transcatheter heart valve (THV) system; 4) grading
scale; and 5) adjudication of events. When PVL was
evaluated before hospital discharge and without central core
laboratory analysis, its absence was reported in 6% to 59% of
patients, whereas moderate or severe PVL was seen in 0% to
24% (1–5,10 –16) (Table 1).
Thus far, only the PARTNER (Placement of Aortic
Transcatheter Valve) trial has used a central echocardiography core laboratory to evaluate PVL (1,2). PVL was graded
in accordance with the American Society of Echocardiography recommendations for native valves (17) because there
were no recommendations for prosthetic valve assessment
at the start of the trial. In addition, because of the
inevitable eccentric nature of the jet and the frequent
“spray” of the jet contour in the outflow tract, the color
Doppler in the available parasternal short-axis view(s)
was weighted in a subjective fashion more heavily than
1126
Généreux et al.
Paravalvular Leak After TAVR
other signals in providing an
integrated assessment. The following definition was applied:
AR ⴝ aortic regurgitation
no PVL (no regurgitant color
AV ⴝ atrioventricular
flow), trace (pinpoint jet in
LV ⴝ left ventricle/
atrioventricular [AV] short-axis
ventricular
view), mild (jet arc length ⬍10%
PVL ⴝ paravalvular leak
of the AV annulus short-axis view
SAVR ⴝ surgical aortic
circumference), moderate (jet arc
valve replacement
length 10% to 30% of the AV
TAVR ⴝ transcatheter
annulus short-axis view circumferaortic valve replacement
ence), and severe (jet arc length
THV ⴝ transcatheter heart
⬎30% of the AV annulus shortvalve
axis view circumference). In the
PARTNER trial, trace/mild PVL
was found in 66% of patients and moderate/severe in
12% (1,2).
Thus far, no prospective direct comparison of the rate of
PVL after TAVR has been published between the 2 most
frequently used THV systems (balloon-expandable THV,
Edwards Lifesciences, Irvine, California; self-expandable
CoreValve THV, Medtronic, Minneapolis, Minnesota).
However, moderate to severe post-procedural PVL seems to
be slightly higher with the CoreValve (9% to 21%) (4–6,18–20)
than the Edwards (6% to 13.9%) (1–3,5,18,21,22) device.
Recent 1-year data presented from the FRANCE 2 (French
Aortic National CoreValve and Edwards 2) Registry seemed to
confirm this finding—the use of self-expandable prosthesis was
identified as one of the major determinants of significant PVL
after TAVR. At patient discharge, self-expandable prosthesis
was associated with a moderate to severe PVL rate of 19.8%,
compared with 12.2% for balloon-expandable prosthesis
(p value not available) (23).
Abbreviations
and Acronyms
Progression Over Time
One of the initial concerns about PVL was potential
worsening during extended follow-up. Because a large
percentage of patients are discharged with trace or mild
PVL, worsening of PVL could have important consequences on the volume load imposed on the left ventricle
(LV), ultimately resulting in significant heart failure. In
addition, if many cases progress to clinically significant
leakage, hemolysis requiring repeated transfusions or reoperation may further complicate the course of patients.
Despite the lack of “common language” among previous
reports in assessment of PVL severity, several studies have
reported comparable findings with respect to time trends of
PVL severity. Webb et al. (24) reported the evolution of
PVL over time in a cohort of 168 patients and found
that PVL was generally mild and remained stable between
30-day and 1-year follow-ups, a result that has been
confirmed by other studies (Table 2). A recent report by
Ussia et al. (16) showed that rates of mild (53%) and
moderate (15%) post-procedural PVL had been reduced to
47% and 10%, respectively, at a follow-up of 3 years. Some
JACC Vol. 61, No. 11, 2013
March 19, 2013:1125–36
attrition of the “sickest” patients might have been due to
patients with worsening PVL dying, but there were no cases
of worsening from mild to moderate/severe regurgitation in
individual patient progression of PVL.
Data from the PARTNER trial suggested, however, that
PVL at 2 years had increased by ⱖ1 grade in 22.4% of
patients, whereas it remained unchanged in 46.2% and
improved by ⱖ1 grade in 31.5% of patients (Fig. 1) (8). So
far, no studies have explored the mechanisms behind improvement or worsening of PVL in individual patients, and
measurement methods may explain, at least in part, these
changes.
Impact on Clinical Outcomes
After SAVR, moderate to severe residual aortic regurgitation (AR) occurs infrequently in approximately 4% of
patients (25). A recent study showed that AR after SAVR
was an independent predictor of long-term mortality with a
hazard ratio of 1.7 (95% CI: 1.2 to 2.3). The TAVR
community has focused extensively on the effect of AR on
survival because its prevalence is much higher after TAVR
than after SAVR (8). A number of studies have identified
AR ⱖ2⫹ to be an independent predictor of short- and
long-term mortality (Table 3) (3). Furthermore, patients
with AR ⱖ2⫹ were 10 times more likely to be nonresponders to therapy at 6 months’ follow-up; nonresponsiveness was defined as either death or New York Heart
Association classification ⱖ2.
Few studies have devoted analyses specifically to PVL.
This is not surprising because the low post-operative rate of
PVL in surgical series makes statistical analysis not meaningful. However, even in TAVR after which postprocedural AR is largely paravalvular, there have been only
a few large registries and randomized trials focused on PVL.
Data on 663 patients from the Italian registry found that
PVL grade ⱖ2⫹ was not associated with early 30-day
mortality, but multivariate analysis did find a hazard ratio of
3.79 for patients with PVL ⱖ2⫹ for late mortality beyond
30 days (6). More disturbingly, although it was generally
believed that only moderate or severe regurgitation would
impact long-term outcomes (26), the recently published
2-year results from the PARTNER trial showed that even
mild PVL was associated with significant mortality (Fig. 2)
(8). Multivariable analyses did not identify AR or PVL as
independent predictors of mortality in this trial, but, interestingly, there is a trend toward improved survival in
patients undergoing TAVR compared with SAVR if PVL
was negligible (70% vs. 65%).
Importantly, based on the current literature, the direct
causal relationship between PVL and mortality (vs. PVL
being a marker for other factors) still needs to be determined. Careful analyses of baseline patient characteristics,
the repercussion of all degrees of PVL on LV geometry and
remodeling, and the determination of the precise cause of
death (cardiovascular vs. noncardiovascular) are needed to
JACC Vol. 61, No. 11, 2013
March 19, 2013:1125–36
confirm the strength and the nature of this relationship. At
this point, any previous observations linking PVL (especially mild) with mortality should be considered hypothesis
generating.
Predictors of PVL
Significant PVL most commonly results from: 1) incomplete prosthesis apposition to the native annulus due to
patterns or extent of calcification (11,27–30) or annular
eccentricity (26); 2) undersizing of the device (10,31,32);
and/or 3) malpositioning of the valve (33). These observations seem to be true for both balloon-expandable and
self-expandable THVs.
Valve sizing has been shown to be one of the strongest
predictors of PVL. A low cover index reflecting a lower
degree of oversizing of the prosthesis based on transthoracic
echocardiography annulus measurement predicts significant
PVL (10). More recently, studies have evaluated the use of
multidetector computed tomography (MDCT) for THV
sizing, and MDCT showed good predictability and reduced
rates of significant PVL (34 –37). Furthermore, larger and
eccentric annuli were identified as predictors of PVL in
multiple studies and most likely reflect inadequate sizing of
the THV (3,15,26). A smaller aortic valve area was found to
predict PVL in one study, but this was likely because the
smaller area indicates a greater degree of calcification (3).
The extent of calcification and asymmetrical distribution, as
well as the location of calcium on the aortic wall, valve
commissure, or THV landing zone, as a predictor for PVL
has been confirmed in several studies (11,26,29,37,38).
In studies specifically evaluating the CoreValve (Medtronic), a
lower depth of implantation and a greater angle between the
aorta and LV outflow tract were found to predict PVL
(14,15).
Assessment of Paravalvular Regurgitation
Angiographic and hemodynamic assessment. Aortic root
angiography is an established tool for qualitative and semiquantitative assessment of AR (39). It is readily available
during the TAVR procedure and can be quickly and safely
executed to provide essential information and initiate adjunctive maneuvers if needed in case of significant (para)
valvular AR. Typically, Sellers criteria are applied to grade
AR (40): 1) grade 1 or mild AR corresponds to a small
amount of contrast entering the LV during diastole without
filling the entire cavity and clearing with each cardiac cycle;
2) grade 2 or moderate AR corresponds to contrast filling of
the entire LV in diastole but with less density compared
with contrast opacification of the ascending aorta; 3) grade
3 or moderate to severe AR corresponds to contrast filling of
the entire LV in diastole equal in density to the contrast
opacification of the ascending aorta; and 4) grade 4 or severe
AR corresponds to contrast filling of the entire LV in
diastole on the first beat with greater density compared with
the contrast opacification of the ascending aorta. During the
Généreux et al.
Paravalvular Leak After TAVR
1127
contrast injection, no material may cross the aortic valve
leaflets (e.g., guidewires, catheters) because incomplete valve
closure may artificially be generated, thus resulting in AR.
Particularly with self-expanding systems, it is important to
wait some time (empirically 10 min) after deployment of the
bioprosthesis to allow the system to expand to its maximum.
The downside of qualitative aortography AR assessment is
that it relies on subjective interpretation of unidimensional
images; therefore, interobserver and intraobserver variability
can be an issue and additional contrast volume required.
Moreover, it is difficult to determine the contribution of
PVL and central AR.
Classic findings of acute AR (acute drop in the aortic
diastolic pressure with or without elevated LV end-diastolic
pressure [LVEDP]) may be seen after TAVR and may be
suggestive of moderate to severe AR. However, these
findings must be interpreted with caution because the
concomitant use of sedatives, vasopressors, inotropes, and
intravenous fluids all impact hemodynamics, and the presence of material through the aortic valve (e.g., wire) may
interfere temporarily with the THV function. Recently, the
AR index, the ratio of the end-diastolic gradient across the
aortic valve bioprosthesis to systolic blood pressure ([ADP ⫺
LVEDP]/ASP; ADP-aortic diastolic pressure, ASP-aortic
systolic pressure), was described (41). An AR index ⬍25
was associated with 1-year mortality. Although this association is interesting, more data and validation are needed to
establish the role of this new index in the therapeutic
decision process after TAVR.
Echocardiographic assessment. Although the native valve
regurgitation quantitative grading scheme has been advocated for the evaluation of prosthetic valve regurgitation
(42), there are limited data to support the use of these
parameters following TAVR. The majority of semiquantitative parameters for assessing AR apply to central regurgitant jets, which are more uniform, making semiquantitative
grading schemes more reliable.
Unlike central jets, paravalvular regurgitant jets are commonly eccentric with crescentic, irregular orifices. Because
these jets occur between the annulus and sewing ring, jet
areas and lengths may not represent the same severity of
regurgitation compared with central jets and these parameters cannot be used to reliably assess regurgitant severity.
Although guidelines suggest using the circumferential extent of the regurgitant jet as a semiquantitative measure of
severity (42), this parameter has not been validated against any
quantitative parameters of regurgitation. Even if we accept the
limited validation of this scheme for surgical prostheses, the
anatomy and physiology of THVs are different than that of
surgical valves. In the balloon-expandable valve, paravalvular
regurgitation should be assessed just below the skirt; for central
jets, the regurgitation should be assessed at the coaptation
point of the leaflets. In addition, there is no scheme that
specifically addresses the unusual regurgitation that accompanies the THV. The intact calcified cusps and annulus signifi-
1128
Selected
Reporting ARReporting
After TAVR
Table 1 Publications
Selected Publications
AR After TAVR
n
74
Abdel-Wahab, 2011 (3)
Sherif, 2010 (14)
John, 2010 (78)
Takagi, 2011 (15)
690
50
100
79
Approach
Prosthesis
Imaging Modality
Severity Gradation
Echocardiogram (TEE)
Site reported (blinded
echocardiographist)
0 ⫽ absent
1 ⫽ trace/mild
2 ⫽ mild/moderate
3 ⫽ moderate/severe
4 ⫽ severe
ES ⫽ 110 (16%)
MCV ⫽ 580 (84%)
Angiogram
Site reported
0 ⫽ absent
1 ⫽ trace/mild
2 ⫽ mild/moderate
3 ⫽ moderate/severe
4 ⫽ severe
—
MCV
Angiogram
Echocardiogram
Site reported
1 ⫽ trivial/mild
2 ⫽ moderate
3 ⫽ moderate/severe
4 ⫽ severe
—
0
1⫹
2⫹
3⫹
4⫹
TF ⫽ 46 (62%)
TA ⫽ 28 (38%)
ES
TF ⫽ 644
TA ⫽ 26
SC ⫽ 22
TAo ⫽ 5
TF
MCV
Angiogram
Echocardiogram
TF ⫽ 62 (78.5%)
SC ⫽ 17
(21.5%)
MCV
Angiogram
Echocardiogram
Site reported
0 ⫽ absent
1 ⫽ mild
2 ⫽ moderate
3–4 ⫽ severe
AR Post-TAVR
Early post-TAVR (TEE)
0 ⫽ 5 (7.0%)
1 ⫽ 53 (72.0%)
2 ⫽ 12 (16.0%)
3 ⫽ 4 (5.0%)
4 ⫽ 0 (0%)
Early post-TAVR (angiogram)
0 ⫽ 191 (27.7%)
1 ⫽ 380 (55.1%)
2 ⫽ 103 (14.9%)
3 ⫽ 14 (2.0%)
4 ⫽ 2 (0.3%)
Early post-TAVR (angiogram)
0 ⫽ 3 (6.0%)
1 ⫽ 27 (54.0%)
2 ⫽ 13 (26.0%)
3 ⫽ 7 (14.0%)
4 ⫽ 0 (0%)
Early post-TAVR (TTE)
0 ⫽ 9 (18.0%)
1 ⫽ 24 (48.0%)
2 ⫽ 13 (26.0%)
3 ⫽ 4 (8%)
4 ⫽ 0 (0%)
Post-dilation ⫽ 34/100
Snare technique ⫽ 4/100
Valve-in-valve ⫽ 3/100
Early post-TAVR (angiogram)
0 ⫽ 35 (35.4%)
1⫹ ⫽ 28 (28.3%)
2⫹ ⫽ 19 (19.2%)
3⫹ ⫽ 8 (0.8%)
4⫹ ⫽ 0 (0%)
Early after adjunctive
technique (angiogram)
0 ⫽38 (38.4%)
1⫹ ⫽ 49 (49.5%)
2⫹ ⫽ 11 (11.1%)
3⫹ ⫽ 1 (0.1%)
4⫹ ⫽ 0 (0%)
Post-dilation ⫽ 21/79
Snare technique ⫽ 1/79
Valve-in-valve ⫽ 2/79
Final result (angiogram)
0 ⫽ 21 (26.6%)
1 ⫽ 42 (53.2%)
2 ⫽ 13 (16.5%)
3 ⫽ 3 (3.8%)
4 ⫽ 0 (0%)
ⱖ2/4 AR
Low cover index
● Operator’s
experience
●
ⱖ2/4 AR
AVA baseline
● Annulus baseline
● Cardiogenic shock
● Renal failure
● Male
●
ⱖ2/4 AR
Increase angle of
LVOT and
ascending aorta
● Depth of device in
relation to
noncoronary cups
●
AgS and DLZ-CS
showed
significant
correlation with
grade of PVL
after initial MCV
deployment
ⱖ2/4 AR
Larger annulus
diameter
● Low implantation
● Peripheral vascular
disease
●
Continued on the next page
JACC Vol. 61, No. 11, 2013
March 19, 2013:1125–36
TF ⫽ 97 (97%)
SC ⫽ 3 (3%)
Adjunctive Techniques
Post-dilation ⫽ 5/74
Valve-in-valve ⫽ 2/74
Généreux et al.
Paravalvular Leak After TAVR
First Author, Year (Ref. #)
Detaint, 2009 (10)
Predictors of AR by
Multivariable
Analysis
Généreux et al.
Paravalvular Leak After TAVR
TF ⫽ 599
Other ⫽ 271
Moat, 2011 (5)
870
ES ⫽ 410 (47%)
MCV ⫽ 459 (53%)
Angiogram
Site reported
Mild
Moderate
Severe
Echocardiogram
Angiogram (If poor
TTE quality)
Site reported
MCV
TF/SC
145
Gotzmann,
2011 (4)
AgS ⫽ Agatston score; AR ⫽ aortic regurgitation; AVA ⫽ aortic valve replacement; CEC ⫽ clinical events committee; DLZ-CS ⫽ device-landing zone calcification score; ES ⫽ Edwards Sapien; LVOT ⫽ left ventricular outflow track; MCV ⫽ Medtronic CoreValve; PVL ⫽ paravalvular
leak; SC ⫽ subclavian; TA ⫽ transapical; TAo ⫽ transaortic; TAVR ⫽ transcatheter aortic valve replacement; TEE ⫽ transesophageal echocardiography; TF ⫽ transfemoral; TTE ⫽ transthoracic echocardiography.
—
AR ⱖ1 ⫽ 516 (61%)
AR ⬎2 ⫽ 115 (13.6%)
—
Conversion to open
surgery ⫽ 6/850
—
Early post-TAVR
Mild ⫽ 64 (44%)
Moderate ⫽ 23 (16%)
Severe ⫽ 2 (1%)
Early post-TAVR
30-day survivors only
Mild ⫽ 55 (45%)
Moderate ⫽ 16 (13%)
Severe ⫽ 0 (0%)
—
—
Post-TAVR
ⱖ2 PVL ⫽ 139 (21.0%)
Post-dilation ⫽ 68/663
Valve-in-valve ⫽ 139/663
Conversion to open
surgery ⫽ 5/663
—
Echocardiogram
Site reported, events
reviewed by
independent CEC
MCV
TF
663
Tamburino,
2011 (6)
First Author, Year (Ref. #)
Continued
Table 1
Continued
n
Approach
Prosthesis
Imaging Modality
Severity Gradation
Adjunctive Techniques
AR Post-TAVR
Predictors of AR by
Multivariable
Analysis
JACC Vol. 61, No. 11, 2013
March 19, 2013:1125–36
1129
cantly influence the location and shape of paravalvular jets;
typically, these jets appear smaller and more irregular at the
level of the intact/calcified cusps and larger just apical to the
THV stent.
Quantitative assessment of total AR, or advanced imaging techniques for assessing paravalvular regurgitant orifices,
may be a more accurate way of assessing severity and thus a
more accurate assessment of risk. Quantitative Doppler uses
comparative flow measurements across a regurgitant valve
and a nonregurgitant valve to calculate regurgitant volume
or fraction (17). The effective regurgitant orifice area is then
calculated by dividing the regurgitant volume by the velocity
time integral of the regurgitant jet continuous wave spectral
profile. Alternatively, the LV stroke volume calculated by
2-dimensional (2D) biplane Simpson method of discs (43) can
be used in place of total (regurgitant plus forward) stroke
volume; however, systematic underestimation of ventricular
volumes has been reported for this method. Although this
quantitative assessment has been largely validated in the
literature (44 –51), has shown reproducibility, and is endorsed
by scientific authorities (17,52), it should be acknowledged that
this assessment is based on 4 parameters, any one of which may
be determined with significant inaccuracy.
Three-dimensional (3D) echocardiography can overcome
the limitations of 2D and standard Doppler measurements
for quantifying regurgitation (43). Pitfalls of 2D LV imaging, including foreshortening, malrotation, and angulation,
can be overcome by 3D imaging. However, limitations of
3D imaging (lower line density and low volume rates) may
reduce the utility of this method for assessing total stroke
volume. Color Doppler 3D volumes can be useful for the
identification and localization of regurgitation jets, as well as
planimetry of the vena contracta area (53,54). This imaging
modality may be particularly useful for post-TAVR assessment of PVL (55,56).
With the increased use of multimodality imaging capable
of 3D reconstruction of the aortic root (36,57– 62), there
has been intense interest in the shape of the annulus and
appropriate sizing of the transcatheter heart valve to reduce
PVL. The oval shape of the annulus has been well documented
(36,60,61,63– 65), and a single sagittal plane measurement is
significantly smaller than the coronary plane measurement.
Algorithms using 3D imaging tools have been suggested to
improve annular sizing and reduce PVL (34,35).
Recently, the Valve Academic Research Consortium
(VARC) published the VARC II definitions and suggested the
use of TAVR-specific criteria for the assessment of AR and/or
PVL after TAVR (Table 4) (66). Figures 2 and 3 illustrate
echocardiographic assessment of PVL after TAVR. Figure 4
illustrates a case using 3D echocardiography assessment of PVL.
Treatment for Significant PVL
Improved positioning of the TAVR could require advanced
imaging techniques for angiographic planning; having the
best coplanar view will ensure accurate fluoroscopic local-
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Paravalvular Leak After TAVR
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Progression
Table 2 Progression
of Aortic and/or
of Aortic
Paravalvular
and/or Paravalvular
RegurgitationRegurgitation
Over Time Over Time
First Author, Year (Ref. #)
n
Significant
Post-Procedural
Significant at
6 Months
Significant at
1 Year
Significant at
2 Years
Significant at
3 Years
—
—
—
—
Paravalvular leakage
Webb, 2009 (24)
168
30 days
2⫹ ⫽ 37%
3⫹ ⫽ 5%
Muñoz-Garcia, 2011 (79)
144
72 h
Mild ⫽ 40%
Moderate ⫽ 23%
Ussia, 2012 (16)
181
Post-procedure
Mild ⫽ 53%
Moderate ⫽ 15%
—
Ye, 2010 (80)
71
30 days
Mild ⫽ 26%
Moderate ⫽ 5%
—
Takagi, 2011 (15)
79
30 days
1⫹ ⫽ 51%
2⫹ ⫽ 20%
3⫹ ⫽ 3%
1⫹ ⫽ 49%
2⫹ ⫽ 27%
3⫹ ⫽ 0%
—
“Stable”
Mild ⫽ 47%
Moderate ⫽ 19%
Ewe, 2011 (81)
107
Post-procedure
1⫹ ⫽ 58%
2⫹ ⫽ 16%
3⫹ ⫽ 5%
ⱖ6 months
1⫹ ⫽ 51%
2⫹ ⫽ 31%
3⫹ ⫽ 0%
Godino, 2010 (82)
137
Post-procedure
1⫹ ⫽ ⬇60%
2⫹ ⫽ ⬇12%
3⫹ ⫽ 4%
4⫹ ⫽ 2%
1⫹ ⫽ ⬇65%
2⫹ ⫽ ⬇9%
3⫹ ⫽ ⬇5%
4⫹ ⫽ 0%
—
Mild ⫽ 48%
Moderate ⫽ 18%
Mild ⫽ 50%
Moderate ⫽ 17%
Mild ⫽ 47%
Moderate ⫽ 10%
—
—
“Remained unchanged
and clinically
insignificant
during follow-up”
—
—
—
—
—
—
—
—
Aortic regurgitation
Bauer, 2010 (83)
88
2⫹ ⫽ 29%
3⫹ ⫽ 7%
—
2⫹ ⫽ 24%
3⫹ ⫽ 0%
Rajani, 2010 (84)
46
Within 5 days
Mild ⫽ 33%
Moderate ⫽ 19%
Moderate/severe ⫽ 5%
—
Mild ⫽ 31%
Moderate ⫽ 8%
Moderate/severe ⫽ 15%
Clavel, 2009 (85)
50
Discharge
Trivial ⫽ 38%
Mild ⫽ 42%
Moderate ⫽ 8%
Severe ⫽ 0%
Lefevre, 2011 (86)
130
Discharge
2⫹ ⫽ 42%
3⫹ ⫽ 5%
Buellesfeld, 2011 (20)
126
30 days
1⫹ ⫽ 32%
2⫹ ⫽ 9%
3⫹ ⫽ 0%
1⫹ ⫽ 39%
2⫹ ⫽ 6%
3⫹ ⫽ 0%
1⫹ ⫽ 34%
2⫹ ⫽ 3%
3⫹ ⫽ 0%
1⫹ ⫽ 37%
2⫹ ⫽ 0%
3⫹ ⫽ 0%
—
Bleiziffer, 2012 (87)
227
Discharge
Mild ⫽ 31%
Mild/moderate ⫽ 13%
Moderate ⫽ 8%
Moderate/severe ⫽ 3%
Mild ⫽ 45%
Mild/moderate ⫽ 11%
Moderate ⫽ 6%
Moderate/severe ⫽ 0%
Severe ⫽ 0%
Mild ⫽ 40%
Mild/moderate ⫽ 16%
Moderate ⫽ 6%
Moderate/severe ⫽ 0.5%
Severe ⫽ 0.5%
Mild ⫽ 41%
Mild/moderate ⫽ 15%
Moderate ⫽ 5%
Moderate/severe ⫽ 1%
Severe ⫽ 1%
—
After implant
1⫹ ⫽ 77%
2⫹ ⫽ 9%
3⫹ ⫽ 5%
Mean 83 ⫾ 80 days
1⫹ ⫽ 82%
2⫹ ⫽ 5%
3⫹ ⫽ 0%
—
—
—
—
Koos, 2011 (29)
57
D’Onofrio, 2011 (88)
504
Gurvitch, 2010 (21)
70
Walther, 2011 (22)
168
6–12 months
Trivial ⫽ 26%
Mild ⫽ 46%
Moderate ⫽ 6%
Severe ⫽ 0%
—
Discharge
1⫹ ⫽ 30%
2⫹ ⫽ 9%
—
Post-procedure
Trivial ⫽ 40%
Mild ⫽ 44%
Moderate ⫽ 6%
—
—
2⫹ ⫽ 23%
3⫹ ⫽ 0%
3–6 months
1⫹ ⫽ 51%
2⫹ ⫽ 1%
3⫹ ⫽ 0%
2⫹ ⫽ 25%
3⫹ ⫽ 0%
—
Mean 9.2 ⫾ 6.5 months
“No changes in the
degree of AR were
found”
—
1⫹ ⫽ 46%
2⫹ ⫽ 5%
3⫹ ⫽ 0%
—
—
—
—
—
—
—
—
—
Trivial ⫽ 60%
Mild ⫽ 33%
Moderate ⫽ 3%
—
Généreux et al.
Paravalvular Leak After TAVR
JACC Vol. 61, No. 11, 2013
March 19, 2013:1125–36
Figure 1
1131
Change in Paravalvular Leak Severity
Over 2-Year Follow-Up
Adapted with permission from Kodali et al. (8).
Figure 2
ization of the valve before implantation. In addition, simultaneous “real-time” imaging, such as echocardiogram (both
2D and 3D), 3D angiographic reconstruction via rotational
aortic root angiogram (67), and the use of novel imaging
systems (68,69), may assist in choosing intraprocedurally the
optimal projection for THV positioning and deployment,
leading potentially to less frequent PVL.
Intraprocedurally, several interventional alternatives to
reduce regurgitation are available (70). Severe calcification
of the native valve might prevent the implanted valve from
expanding completely against the annulus, leaving residual
orifices through which PVL may occur. Post-implantation
balloon dilation of the valve might be effective in reducing
PVL and may be considered the initial option for patients
with PVL (71). A slightly oversized balloon is recommended to fully expand the valve. Studies have shown that
post-dilation can be safely performed, with a reduction of
the regurgitation in a majority of patients (38). Calcification
of the valve significantly influences the success of this
intervention. However, in some patients, post-dilation has
no effect in reducing AR (15); in addition, post-dilation has
been shown to be associated with a higher incidence of
cerebrovascular events (38). The effect of post-dilation on
survival has yet to be determined.
Impact of Paravalvular Leak
on 2-Year All-Cause Mortality
Reprinted with permission from Kodali et al. (8). HR ⫽ hazard ratio.
Especially with the CoreValve, implantation of the valve
that is too low is associated with PVL. Repositioning to a
higher implantation depth could therefore reduce PVL.
However, no retrievable valve is currently available on the
market. Therefore, a snaring maneuver has been described, in which the valve is pulled up by attaching a
snare to one of the frame loops (72,73). Although
successful cases have been reported (74), the valve may
also move to the original (too low) position as soon as
tension is released (70). An extra word of caution is
warranted when the snaring technique is considered in
patients with extensively calcified valves because chunks
of calcium may detach as a result of friction. Furthermore, there is a risk of damaging the ascending aorta
during the snaring maneuver.
A valve-in-valve procedure may be necessary in some
cases in which post-dilation or other techniques do not
improve the degree of PVL. This is specifically indicated for
patients in whom the valve was suboptimally positioned
(i.e., too shallow or too deep). In the Italian registry, a
valve-in-valve procedure was used in 3.6% of 663 patients
Outcomes
Aortic and/or
Paravalvular
RegurgitationRegurgitation
Table 3 Associated
Outcomes With
Associated
With Aortic
and/or Paravalvular
First Author, Year (Ref. #)
n
Variable
Outcome
Abdel-Wahab, 2011 (3)
690
AR ⱖ2
In-hospital mortality
Gotzmann, 2011 (4)
122
AR ⱖ2
6-month mortality
No clinical improvement
Takagi, 2011 (15)
Hayashida, 2012 (89)
Leber, 2011 (90)
Univariate Analysis
OR ⫽ 2.50 (95% CI 1.37–4.55)
—
Multivariate Analysis
OR ⫽ 2.43 (95% CI 1.22–4.85)
OR ⫽ 4.26 (95% CI 1.59–11.45)
OR ⫽ 10.1 (95% CI 3.20–31.94)
41
AR ⱖ2
6-month mortality
12.2% vs. 25.0% (p ⫽ 0.25)
—
260
AR ⱖ2
Median 217 days (IQR: 54–401)
HR ⫽ 1.97 (95% CI 1.19–3.28)
—
69
AR ⬎2
1-year mortality
9% vs. 37.5% (95% CI p ⫽ 0.07)
Moat, 2011 (5)
870
AR ⱖ2
1-year mortality
HR ⫽ 1.49 (95% CI 1.00–2.21)
Sinning, 2012 (91)
152
PVL ⱖ2
1-year mortality
HR ⫽ 4.0 (95% CI 2.1–7.5)
Tamburino, 2011 (6)
663
PVL ⱖ2
Late mortality
Sinning, 2012 (41)
146
Moderate/severe PVL
1-year survival
HR ⫽ 3.9 (95% CI 2.0–7.5)
Unbehaun, 2012 (26)
358
No vs. trace vs. mild AR
2-year survival
66% vs. 72% vs. 67% (p ⫽ 0.77)
Kodali, 2012 (8)
158
Mild to severe AR
2-year survival
HR ⫽ 1.75 (95% CI 1.17–2.61)
Not significant
Mild to severe PVL
2-year survival
HR ⫽ 2.11 (95% CI 1.43–3.10)
Not significant
HR ⫽ hazard ratio; IQR ⫽ interquartile range; OR ⫽ odds ratio; other abbreviations as in Table 1.
—
—
HR ⫽ 1.66 (95% CI 1.10–2.51)
HR ⫽ 4.9 (95% CI 2.5–9.6)
HR ⫽ 3.79 (95% CI 1.57–9.10)
HR ⫽ 2.4 (95% CI 1.0–5.4)
—
1132
Généreux et al.
Paravalvular Leak After TAVR
JACC Vol. 61, No. 11, 2013
March 19, 2013:1125–36
VARC
for Evaluation
Aortic and/or
Paravalvular
RegurgitationRegurgitation
After TAVR After TAVR
TableII4Recommendations
VARC II Recommendations
forofEvaluation
of Aortic
and/or Paravalvular
Mild
Moderate
Severe
Absent or brief early diastolic
Intermediate
Prominent, holodiastolic
⬍10
10–29
Semiquantitative parameters
Diastolic flow reversal in the descending aorta—pulsed wave
Circumferential extent of prosthetic valve paravalvular regurgitation (%)*
ⱖ30
Quantitative parameters†
Regurgitant volume (ml/beat)
⬍30
30–59
ⱖ60
Regurgitant fraction (%)
⬍30
30–49
ⱖ50
Effective regurgitant orifice area (cm2)
0.10
0.10–0.29
*Not well validated and may overestimate severity compared with quantitative Doppler. †For LVOT ⬎2.5 cm, significant stenosis criteria is ⬍0.20.
VARC ⫽ Valve Academic Research Consortium; other abbreviations as in Table 1.
(75). Compared with patients who were implanted with a
single valve, those who underwent valve-in-valve had similar
safety and efficacy over a 1-year follow-up. Encouraging
results have been reported from other series as well (76).
As a final option for patients with continued severe PVL
in whom interventional therapy does not suffice, conversion
to conventional SAVR may be needed (77). SAVR may be
undesirable because these patients are generally at high or
extreme risk, but the procedure may be unavoidable in some
cases.
Figure 3
ⱖ0.30
Adapted with permission from Kappetein et al. (66).
Emerging TAVR Technologies
Currently, there is no proven or generally accepted treatment for PVL. However, there are emerging THV systems
and technologies that are promising in minimizing PVL
after TAVR (Fig. 5). These devices may reduce PVL by
better supra-, infra-, or intra-annular sealing (cuff) or by
allowing controlled deployment, repositioning, or removal
of the THV. Preimplantation calcification debulking (surgically or not) also remains one of the most interesting areas
Quantitative Doppler Echocardiography Can Be Used to Calculate the Regurgitant Orifice and Volume
(A) Post–transcatheter heart valve (THV) left ventricular outflow tract (LVOT) diameter (just apical to the THV stent). (B) Right ventricular outflow tract (RVOT) diameter.
(C) LVOT Doppler with sample volume located just apical to the THV stent aligned in the short-axis view of the LVOT pulsed Doppler signal just below the THV stent.
Stroke volume (SV) across the THV ⫽ LVOT area ⫻ LVOT velocity time integral (VTI) ⫽ 56 ml. (D) RVOT VTI yields an SV across the RVOT of 43 ml. The regurgitant volume ⫽ LVOT SV ⫺ RVOT SV ⫽ 13 ml. AR ⫽ aortic regurgitation; PG ⫽ pressure gradient.
JACC Vol. 61, No. 11, 2013
March 19, 2013:1125–36
Figure 4
Généreux et al.
Paravalvular Leak After TAVR
1133
3-Dimensional Echocardiography Can Be Used to Quantitate the Regurgitant Orifice and Volume
(A) Multiplanar reconstruction of a 3-dimensional color Doppler volume set, aligned in the short-axis view of the LVOT just below the THV stent. The planimetered regurgitant
orifices are 4 mm2 and 1 mm2, consistent with a total effective regurgitant orifice area (EROA) of 5 mm2. (B) Aortic regurgitant continuous wave spectral Doppler with AR VTI of
190 ms. The regurgitant volume ⫽ EROA ⫻ AR VTI ⫽ 10 ml (same patient as in Fig. 3). Abbreviations as in Figure 3.
of development to ensure adequate THV expansion and
annulus sealing.
Limitations of the Current Literature
Many limitations of the current literature should be acknowledged. Although some studies have used echocardi-
Figure 5
ography, others have used angiography to assess PVL
immediately after THV implantation, making comparison
between studies difficult. Most of the studies have used site
self-reported PVL severity and lack independent adjudication of clinical events. Although the PARTNER trial had
the advantage of a central echocardiography core laboratory
Emerging TAVR Devices Involving Improved Technologies, Potentially Minimizing PVL After TAVR
(A) SAPIEN 3 (Edwards Lifesciences, Irvine, California). (B) CENTERA (Edwards Lifesciences). (C) Direct Flow Medical (Direct Flow Medical, Santa Rosa, California).
(D) Portico (St. Jude Medical, St. Paul, Minnesota). (E) Engager (Medtronic, Minneapolis, Minnesota). (F) Heart Leaflet Technologies (Heart Leaflet Technologies,
Maple Grove, Minnesota). (G) JenaValve (JenaValve Technology, Munich, Germany). (H) Sadra Lotus Medical (Boston Scientific SciMed Inc., Maple Grove, Minnesota).
1134
Généreux et al.
Paravalvular Leak After TAVR
and adjudication of clinical events, we are still waiting for
in-depth analysis of the outcomes associated with PVL.
Baseline characteristics of patients with no/trace PVL may
be different than those with mild to severe PVL and may
explain the difference in mortality and the absence of PVL
as a predictor for mortality in several reported multivariable
analyses. Finally, better criteria to establish PVL severity are
needed to ensure appropriate classification and uniformity
among studies.
Conclusions
The association of PVL after TAVR with mortality has
made it the new “in vogue” Achilles’ heel of TAVR.
Although post-procedural moderate to severe PVL can
understandably be a predictor of a worse outcome, the
association with mild PVL may be debatable. Given the
limitations of the current literature, the nature and strength
of the relationship between PVL and mortality are still to be
determined. Future studies should standardize the evaluation of PVL and ensure an appropriate classification of its
severity. Upcoming THV systems should be designed to
minimize PVL, and emerging technology, such as noninvasive calcification debulking of the aortic valvular complex,
brings promises of lower PVL rates after TAVR, potentially
as low as those after SAVR.
Reprint requests and correspondence: Dr. Martin B. Leon,
Columbia University Medical Center, New York-Presbyterian
Hospital, 177 Fort Washington Avenue, New York, New York
10032. E-mail: mleon@crf.org.
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Key Words: aortic stenosis y paravalvular leak y TAVI y TAVR.